Method for preparing phenyloxymethyl-nitro-imidazole derivatives and use of same

Abstract

Fexinidazole is prepared according to a method which comprises the following steps: a) reacting 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride in the presence of a suspension of powdered alkaline carbonate in an anhydrous organic solvent suitable for performing nucleophile substitution reactions; b) adding to the resulting reaction medium a solution of 4-methyl-mercapto-phenol in the same organic solvent as referred to in step a); c) separating fexinidazole from the reaction mixture as its hydrochloride salt and d) converting said hydrochloride salt into fexinidazole and optionally, purifying the latter.

The invention claimed is: 
     
       1. A method for preparing 1-methyl-2-(4-methylmercapto-phenyloxymethyl)-5-nitro-imidazole having the formula 
       
         
           
           
               
               
           
         
         which comprises the steps of: 
         a) reacting 1-methyl-2-hydroxymethyl-5-nitro-imidazole with methanesulfonyl chloride in the presence of a suspension of powdered alkaline carbonate in an anhydrous organic solvent suitable for performing nucleophile substitution reactions while keeping the reaction medium at a temperature not exceeding 20° C. so as to afford less than 3 area percent, relative to the total area of the resulting reaction components of step a) detected by liquid chromatography, of each of the following secondary compounds of formula 
       
       
         
           
           
               
               
           
         
         b) adding to the resulting reaction medium a solution of 4-methylmercapto-phenol in the anhydrous organic solvent used in step a) while keeping the reaction medium at a temperature not exceeding 30° C. so as to avoid dimerization of the compound of formula I into the compound of formula 
       
       
         
           
           
               
               
           
         
          and heating thereafter the resulting reaction mixture up to 50° C.; 
         c) separating the compound of formula I from the reaction mixture as its hydrochloride salt; and 
         d) converting said hydrochloride salt into the compound of formula I and, optionally, purifying the compound of formula I. 
       
     
     
       2. The method of  claim 1 , wherein the anhydrous organic solvent suitable for performing nucleophile substitution reactions is a polar aprotic organic solvent. 
     
     
       3. The method of  claim 2 , wherein the polar aprotic organic solvent is an aliphatic ketone. 
     
     
       4. The method of  claim 1 , wherein the powdered alkaline carbonate is potassium carbonate. 
     
     
       5. The method of  claim 1 , which comprises adding 4-methylmercapto-phenol, in the form of a solution in the same solvent used in step a), to the reaction mixture resulting from step a) while keeping the reaction medium at a temperature not exceeding 25° C., and heating thereafter the resulting reaction mixture up to 40° C. 
     
     
       6. The method of  claim 1 , which further comprises adding preheated water to the reaction mixture resulting from step b) prior to transforming the compound of formula I into its hydrochloride salt according to step c). 
     
     
       7. The method of  claim 1 , which comprises filtering off said hydrochloride salt from the reaction mixture resulting from step c), and in step d) subsequently subjecting said hydrochloride salt to alkalinisation by means of ammonia in an aqueous organic media. 
     
     
       8. The method of  claim 2 , wherein the polar aprotic organic solvent is a C3 to C5 aliphatic ketone. 
     
     
       9. The method of  claim 2 , wherein the polar aprotic organic solvent is acetone or acetonitrile.